Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:10]2[CH2:9][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([OH:8])[CH:4]=3)[NH:1][C:24]2=[O:25])[CH2:16][CH2:15]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1ccc(O)cc1CNC1CCN(Cc2ccccc2)CC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(O)cc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
A stirred solution of 4-amino-3-[(1-benzyl-piperidin-4-yl-amino)-methyl]phenol (0.16 g, 0.51 mmol) in tetrahydrofuran (3 mL) at 0° C. was treated with carbonyl diimidazole (52 mg, 0.51 mmol). The reaction was stirred for 30 min at 0° C. and at reflux for 1 h. After cooling to room temperature, the solvent was evaporated and the residue purified by column to afford 100 mg (57%) of the desired product. LC/MS: tR=1.09 min, 338.28 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[CH2:17]([S:19]([NH-:22])(=[O:21])=[O:20])[CH3:18].Cl>CS(C)=O>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: CCS([NH-])(=O)=O
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1ncnc(Cl)c1-c1ccc(C)cc1
Reaction time: 14 h
Yield: 39.6 %

Procedure:
4,6-dichloro-5-(p-tolyl)-pyrimidine (717 mg) was dissolved in DMSO (5 ml) and ethanesulfonamide potassium salt (927 mg) was added and stirring continued for 14 h at rt. The solution was poured onto ice/water and acidified by 2 N HCl to pH 3-4. The precipitate was filtered off and washed with water and diethylether to give ethanesulfonic acid (6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (370 mg) as a white powder. LC-MS: tR: 4.09, [M+H]+: 312.10.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C.O>[CH3:2][N:1]([C:21]([O:20][CH:16]([O:15][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])[CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: CNCC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(C)C(OC(=O)c1ccccc1)OC(=O)N(C)CC(=O)O
Yield: 39.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.345 g, 3.8 mmols) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (1 g, 2.98 mmol) were reacted in an acetonitrile/water mixture (20 mL) to provide 0.364 g (39.5% yield) of the title compound (48) as a colorless, waxy material after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.05 (t, 2H), 7.59 (t, 1H), 7.43 (t, 2H), 6.84 (m, 1H), 4.21-3.88 (br m, 2H), 3.0 (d, 3H), 2.25 (m, 1H), 1.15 (dd, 6H). MS (ESI) m/z 332.20 (M+Na)+; 308.21 (M−H)−.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2].[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:14][C:13]1([CH3:33])[CH3:32])(=[O:11])[CH3:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([NH:8][CH2:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])=[O:23])=[CH:19][CH:20]=2)[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:14][C:13]1([CH3:33])[CH3:32])(=[O:11])[CH3:10]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)OCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(C(=O)NCCCOC(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of 3-isopropoxypropylamine (5.2 mg) with 1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylic acid (10 mg), under the agency of HATU (23 mg) and N,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[C:19]([C:23]4([C:29](N)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:5]=1>CO.O1CCCC1>[CH3:3][C:4]1[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[C:19]([C:23]4([C:29]([OH:1])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:5]=1
Reactant: [OH-]
Reactant: Cc1nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c(=O)[nH]1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(-c2ccc(Sc3cccc(C4(C(=O)O)CCOCC4)c3)cc2)c(=O)[nH]1

Procedure:
Potassium hydroxide (3.0 mmol) is added to a solution of 4-(3-{[4-(3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carboxamide (1.0 mmol) (example 10) in methanol and tetrahydrofuran (1:2) and the reaction mixture is refluxed for about 18 hours. The solvent is evaporated under vacuum. A small amount of water and concentrated hydrochloric acid are added to the residue to separate out the title compound.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C(F)(F)F)=[C:9](OC)[CH:8]=1.[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O.CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:2][C:3](=[O:5])[CH3:4])=[C:9]([O:25][CH3:22])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)CCl
Reactant: COc1cc(Br)ccc1NC(=O)C(F)(F)F
Agent: [Cs+]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)ccc1NCC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Chloroacetone (20 g) was added dropwise to a DMF (160 mL) suspension of N-(4-bromo-2-methoxyphenyl)-2,2,2-trifluoroacetamide (32.4 g), cesium carbonate (71 g) and potassium iodide (1.8 g), and the reaction solution was agitated at room temperature for 2 hours. Then, The reaction solution was stirred for 1 hour and iced water was added thereto. Crystals deposited were separated by filtering. The obtained crystal was suspended in methanol (360 mL) and 2N sodium hydroxide solution (55 mL), and the suspension was agitated for 30 minutes. An iced water was added thereto. Crystals deposited were separated by filtering, and air-dried overnight. 25.2 g of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([OH:17])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.C1(C)C(C(Cl)=O)=CC=CC=1.[NH3:34]>CC(C)=O>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([NH2:34])=[O:17])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)O
Reactant: N
Agent: Cc1ccccc1C(=O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(N)=O

Procedure:
o-Toluoyl chlorides may be prepared by reacting 3,5-dinitro-4-chloro-o-toluic acid with phosphorus pentachloride. The resulting o-toluoyl chloride is then treated with ammonia in cold acetone to yield the corresponding 3,5-dinitro-4-chloro-o-toluamide which is converted to the corresponding nitrile by reaction with phosphorus pentoxide or preferably with POCl3.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+]([C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:11]1[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=1)[C:15]#[N:16]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Sc2ccccn2)cc1C#N

Procedure:
10 g of 2-mercaptopyridine, 14.2 g of 4-nitrophthalonitrile, and 22.6 g of potassium carbonate were suspended in 250 ml of acetone and heated at reflux temperature for 4 hours. The solution was filtered through a pad of celite and a course glass filter to remove residual solids. The solution was concentrated to a crude residue and purified by column chromatography on silica gel eluting the product with a gradient of 0-10% ethyl acetate in dichloromethane. 6.4 g of product was recovered; 1H NMR (200 Mz, CDCl3) δ=8.49-8.53 (m, 1H), 7.84-7.83 (dd, 1H), 7.76-7.71 (m, 2H), 7.68-7.64 (dd, 1H), 7.40-7.36 (dt, 1H), 7.27-7.20 (m, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[S:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([CH2:39][C:40]2[S:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2ccc(Cl)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(Cl)s2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.64 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(5-chloro-2-thienyl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.32 g, 45%).
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][Cl:23])[O:17][C@H:16]([CH2:18][Cl:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@H:9]([OH:24])[C@@H:8]([OH:25])[C@H:7]1[Cl:26])=O.C[O-].[Na+]>CO>[CH2:5]([OH:4])[C@@H:6]1[O:11][C@H:10]([O:12][C@:13]2([CH2:22][Cl:23])[O:17][C@H:16]([CH2:18][Cl:19])[C@@H:15]([OH:20])[C@@H:14]2[OH:21])[C@@H:9]([OH:24])[C@@H:8]([OH:25])[C@H:7]1[Cl:26]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@@H]1O[C@H](O[C@]2(CCl)O[C@H](CCl)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)[C@H]1Cl
Reaction time: 4 h
Yield: 66.5 %

Procedure:
To a solution of 15.8g of sucralose-6-acetate and 120g of methanol was added by 0.15g of sodium methoxide. The reaction mixture was stirred at 30° for 4 hours. Then, the reaction mixture was neutralized to pH7, filtered and then the filtrate was decolored with activated carbon and concentrated under vacuum condition to afford the crude sucralose. The crude was recrystallized from water to afford 9.5g of pure sucralose with over 99% purity.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH2:61][OH:62])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@:22]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH3:59])=[C:53]([F:60])[CH:52]=3)[CH:44]=2)([O:41][CH3:42])[O:21][C@@H:20]1[CH:61]=[O:62])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Oxalyl chloride (1.17 mL, 13.6 mmol) was dissolved in 20 mL dichloromethane and cooled to −78° C., followed by dropwise addition of a solution (20 mL) of dimethyl sulfoxide (1.56 mL, 21.9 mmol) in dichloromethane and a solution (50 mL) of [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 4i (7.6 g, 10.45 mmol) in dichloromethane. The reaction mixture was stirred for 30 minutes at −78° C. Triethylamine (7.25 mL, 52.3 mmol) was added before the reaction mixture was warmed and stirred for 2 hours at room temperature. Thereafter, the reaction mixture was partitioned after 50 mL 1 M hydrochloric acid were added. The organic extract was washed with saturated sodium chloride solution (50 mL×2). The aqueous phase was extracted with dichloromethane (50 mL). The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 4j (7.58 g, colourless grease), which was used directly without purification in the next step.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24].CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:25][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[C:7]1=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CNCC4C3)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(CC2CC2(F)F)c2ccc(C3=CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-[(2,2-Difluorocyclopropyemethyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (14-2, 50 mg, 0.14 mmol, 1.0 equiv), and DIPEA (0.076 mL, 0.43 mmol, 3.0 equiv) were added to anhydrous methylene chloride (2 mL). Stirred for 5 min and methanesulfonyl chloride (12.0 μL, 0.16 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 15-1 as a pale yellow oil. MS m/z (M+H): calculated=425.1456; observed=425.1465.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20])=[O:4].[OH-].[Na+].Cl>CO.O.CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[NH:7][C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 77.5 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.050 g, 0.147 mmol) in methanol (1.5 mL) was added 1 M NaOH (1.47 mL, 1.47 mmol). The reaction mixture was stirred at 75-80° C. for 2 days. The reaction mixture was diluted with H2O and the pH was adjusted with 1 M HCl until 1-2. The reaction mixture was diluted with EtOAc and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. The crude product was triturated with diethyl ether/dichloromethane and the resulting solid was collected and dried under vacuum to yield 0.033 g (69%) pure desired product as a yellow solid. MS ESI (+) m/z 327, 329 (M+, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 13.1 (br s, 1H), 11.5 (s, 1H), 10.9 (s, 1H), 8.77 (br s, 1H), 8.10 (d, 1H), 7.59 (d, 1H), 7.35 (d, 1H) 6.16 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][OH:28])[O:24][C:23]4=[O:29])=[CH:17][C:16]=3[F:30])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:31])[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:16]([F:30])=[CH:17][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][O:28][S:40]([CH3:39])(=[O:42])=[O:41])[O:24][C:23]4=[O:29])=[CH:19][C:20]=3[F:21])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](CO)OC4=O)cc3F)CC2)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](COS(C)(=O)=O)OC4=O)cc3F)CC2)O1
Reaction time: 2 h
Yield: 93 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4yl)-3,5-difluorophenyl)-5(R)-hydroxymethyloxazolidin-2-one (2.19 g, 5 mM) was dissolved in dry dichloromethane (40 ml) under nitrogen at 0°, and treated with triethylamine (0.81 g, 8 mM). Methanesulfonyl chloride (0.687 g, 6 mM) was added, and stirring continued for 2 hours, allowing the temperature to rise to ambient. Aqueous sodium bicarbonate (5%, 20 ml) was added, and stirring continued for 10 minutes. The organic phase was separated, dried (magnesium sulfate), filtered, and evaporated to dryness. The resulting gum was triturated with diethyl ether (50 ml) and solid filtered to give the title compound (2.4 g). NMR (DMSO-d6) δ: 1.30 (s, 3H); 1.33 (s, 3H); 2.30 (br, 1H); 2.39 (br, 1H); 3.26 (s, 3H); 3.67 (t overlapping m, 2H); 3.82 (dd, 1H); 4.01-4.31 (complex overlapping m, 5H); 4.45 (dd, 1H); 4.51 (dd, 1H); 4.90 (dd, 1H); 5.03 (m, 1H); 5.87 (s, 1H); 7.35 (d, 2H). MS (ESP): 517 (MH+) for C22H26F2N2O8S
Reaction SMILES: [ClH:1].CC1ON=C(C2C=CC(C3OCCNCC3)=CC=2)N=1.C([N:28]1[CH2:34][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[O:45][N:44]=[CH:43][N:42]=3)=[CH:37][CH:36]=2)[CH2:32][O:31][CH2:30][CH2:29]1)C1C=CC=CC=1>>[ClH:1].[O:45]1[C:41]([C:38]2[CH:39]=[CH:40][C:35]([CH:33]3[CH2:32][O:31][CH2:30][CH2:29][NH:28][CH2:34]3)=[CH:36][CH:37]=2)=[N:42][CH:43]=[N:44]1
Reactant: c1ccc(CN2CCOCC(c3ccc(-c4ncno4)cc3)C2)cc1
Agent: Cc1nc(-c2ccc(C3CCNCCO3)cc2)no1
Agent: Cl
Product: c1noc(-c2ccc(C3CNCCOC3)cc2)n1

Procedure:
6-(4-[1,2,4]Oxadiazol-5-yl-phenyl)-[1,4]oxazepane hydrochloride was prepared by the same procedure as that of 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-[1,4]oxazepane hydrochloride except for utilizing 4-benzyl-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepane instead of 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-4-(1-phenyl-ethyl)-[1,4]oxazepane 6-(4-[1,2,4]Oxadiazol-5-yl-phenyl)-[1,4]oxazepane hydrochloride was obtained as white solid (0.03 g, 0.09 mmol, 90%).
Reaction SMILES: NO.[CH2:3]([OH:5])[CH3:4].[OH:6][NH:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[C:20]([OH:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[NH:9].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:3]([O:6][NH:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]1[C:20]([OH:31])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[NH:9])(=[O:5])[CH3:4]
Reactant: N=C(NO)n1c(-c2cccc(-c3ccccc3)c2O)cc2ccccc21
Reactant: CCO
Agent: NO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)ONC(=N)n1c(-c2cccc(-c3ccccc3)c2O)cc2ccccc21

Procedure:
The cyano group in compound 15 is then converted into the carbamimidoyl group by first treating 15 with hydrogen chloride gas in an anhydrous alcoholic solvent such as methanol, ethanol and the like, and then treating the resulting (5-methoxycarbonimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole 16 with an inorganic base such as ammonium carbonate, and the like in an alcoholic solvent such as methanol, ethanol, or with excess ammonia to give resulting (5-carbamimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole of Formula I. Alternatively, compound 15 can be converted to a compound of Formula I by first refluxing it with hydroxylamine in an alcoholic solvent such as ethanol and then treating the resulting (N-hydroxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole with acetic anhydride in acetic acid to give (N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole. The acetoxy group is then removed under hydrogenation reaction conditions by treating N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole with 10% palladium in an alcoholic solvent such as methanol, ethanol, and the like.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[C@H:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[CH2:7]1.C(N(CC)CC)C.[CH3:44][S:45]([Cl:48])(=[O:47])=[O:46]>ClCCl>[ClH:48].[F:22][C:19]([F:21])([F:20])[C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([C:23]([F:24])([F:26])[F:25])[CH:16]=1)[C:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][NH:3][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:7][C@H:8]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:27]
Reactant: Cc1ccc(C[C@@H]2CN(CCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCNS(C)(=O)=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (2R)-4-(2-aminoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (110 mg), triethylamine (0.2 ml) in dichloromethane (10 ml) was added methanesulfonyl chloride (0.1 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with aqueous saturated sodium bicarbonate solution and brine, and dried. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (40:1) and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(mesylamino)ethyl]piperazine hydrochloride (50 mg).